Effects of the beta 2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia

Abstract

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 10 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta agonist formoterol in the cachectic muscles through several key biological pathways.

Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function

“…autophagy flux, supporting the idea that direct blockade of protein degradation should not be pursued. Few studies tried to uncover the mechanism underlying formoterol effect on muscle proteolysis in both healthy [24] and wasting (cancer-related) conditions [25,26] Consistently, survival of tumor-bearing mice is not impaired when autophagy is induced in the skeletal muscle by TP53INP2 overexpression, at least in the experimental settings adopted in this study, despite muscle protein depletion is exacerbated. Previous data suggested that TP53INP2 repression was part of an adaptive mechanism aimed at preserving muscle mass upon insulin deficiency or insulin resistance [10,17].…”

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…An adaptive response to oxidative stress is also induced by formoterol, a b2-adrenoceptor-selective agonist. Several studies report the beneficial effects of this compound in reverting cancer-induced muscle wasting in both animal models and cancer patients by triggering protein metabolism toward synthesis and reducing inflammation (53,92,114,136,137). Along with the anabolic/anticatabolic effects, formoterol also prevents the increase of oxidized proteins and MDA/HNE-protein adducts in the skeletal muscle of Yoshida AH-130-bearing rats (115).…”

MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia

“…Busquets et al . observed a ß 2 ‐adrenergic agonist to reduce the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscle (GAS), thus contributing to the observed anti‐wasting effects …”